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Updated: May 10, 2026
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from
Douglas D Fang1, Cathy C Zhang, Yin Gu
1Oncology Research Unit, Pfizer Global Research & Development, San Diego, California, United States of America.
Abstract:
PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) mutations can help predict the antitumor activity of phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibitors in both preclinical and clinical settings. In light of the recent discovery of tumor-initiating cancer stem cells (CSCs) in various tumor types, we developed an in vitro CSC model from xenograft tumors established in mice from a colorectal cancer patient tumor in which the CD133+/EpCAM+ population represented tumor-initiating cells. CD133+/EpCAM+ CSCs were enriched under stem cell culture conditions and formed 3-dimensional tumor spheroids. Tumor spheroid cells exhibited CSC properties, including the capability for differentiation and self-renewal, higher tumorigenic potential and chemo-resistance. Genetic analysis using an OncoCarta™ panel revealed a PIK3CA (H1047R) mutation in these cells. Using a dual PI3K/mTOR inhibitor, PF-04691502, we then showed that blockage of the PI3K/mTOR pathway inhibited the in vitro proliferation of CSCs and in vivo xenograft tumor growth with manageable toxicity. Tumor growth inhibition in mice was accompanied by a significant reduction of phosphorylated Akt (pAKT) (S473), a well-established surrogate biomarker of PI3K/mTOR signaling pathway inhibition. Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R) mutant CSCs and their derivatives. These results may assist in the clinical development of PF-04691502 for the treatment of a subpopulation of colorectal cancer patients with poor outcomes.
Insights
Targeting PIK3CA mutant colorectal cancer stem cells (CSCs) with the PI3K/mTOR inhibitor PF-04691502 shows potent antitumor activity. This dual inhibitor effectively reduced tumor growth and CSC proliferation, offering a potential new treatment for specific colorectal cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Research
Background:
- PIK3CA mutations predict response to PI3K/mTOR inhibitors.
- Cancer stem cells (CSCs) drive tumor initiation and resistance.
- Colorectal cancer (CRC) remains a significant health challenge.
Purpose of the Study:
- To develop and characterize an in vitro colorectal cancer stem cell (CSC) model.
- To evaluate the efficacy of the dual PI3K/mTOR inhibitor PF-04691502 against PIK3CA-mutant CSCs.
- To assess the therapeutic potential of PF-04691502 in preclinical models of colorectal cancer.
Main Methods:
- Established an in vitro CSC model from patient-derived xenografts (CD133+/EpCAM+).
- Utilized genetic analysis to identify PIK3CA (H1047R) mutation in CSCs.
- Administered PF-04691502 to inhibit PI3K/mTOR signaling in vitro and in vivo.
Main Results:
- The CSC model exhibited stem cell properties, including self-renewal and chemo-resistance.
- PIK3CA (H1047R) mutation was confirmed in the CSCs.
- PF-04691502 inhibited CSC proliferation and xenograft tumor growth, reducing pAKT levels.
- Manageable toxicity was observed in vivo.
Conclusions:
- PF-04691502 demonstrates potent anticancer activity against PIK3CA (H1047R) mutant colorectal cancer stem cells.
- Targeting the PI3K/mTOR pathway with PF-04691502 is a promising strategy for a subset of CRC patients.
- These findings support the clinical development of PF-04691502 for refractory colorectal cancer.
